Transdermal drug delivery provides several important advantages over traditional oral and intravenous delivery routes as it bypasses the liver in terms of first pass elimination, avoids the inconvenience of intravenous therapy, provides less chance of dosage errors, permits steady absorption of drugs over longer time periods and enables both local and systemic treatment effects. A variety of transdermal drug delivery systems are currently available in the market and/or in developmental stage that use a single source of energy to enhance skin permeability and have limitations in their applicability. Transdermal drug delivery systems depend on a variety of well established technologies and transport mechanisms to facilitate the migration of drugs across the skin membrane. Despite the advances made in transdermal delivery systems, skin permeability (especially for larger molecules such as insulin and vaccines) and the controlled delivery of smaller molecules with desirable/programmable release profiles (e.g., pulsatile delivery) on a single platform is not available.
For example, T. Stanley et. al (U.S. Pat. No. 6,261,595) discusses a transdermal drug delivery system comprising a heating element, where the application of heat facilitates the active transport of the drug across the skin membrane. Recently, J. Park et. al. (International Journal of Pharmaceutics, 2008, 359, 94-103) reported that exposing the skin to higher temperatures (>100° C.) for shorter times (less than a second) leads to higher skin permeability without damaging the skin. Heat induced delivery enhances kinetic energy of drug molecules and the proteins, lipids, and carbohydrates in the cell membrane leading to higher skin permeability, body fluid circulation, blood vessel wall permeability, and drug solubility. Heating prior to or during topical application of a drug dilates the penetration pathways in the skin, while heating the skin after the topical application of a drug increases the drug absorption into the vascular network, enhancing the systemic delivery but decreasing the local delivery as the drug molecules are carried away from the local delivery site. Further, it is also possible that application of focused thermal energy in short bursts (>100° C.) porate the skin (thermal ablation of stratum corneum) and enable drug permeation.
It has been established that application of ultrasound radiation/pressure on the skin also increases transdermal penetration rate. The mechanism of action was attributed to micro channel formation via cavitation and/or radiation pressure onto the drug (U.S. Pat. No. 5,421,816). The idea of using electrically assisted transmembrane drug delivery (e.g., iontophoresis) was described by L. A. McNichols in the U.S. Pat. No. 5,697,896, where the electromotive force (repulsive charges) act upon drug molecules charged or uncharged or mixture thereof. Electroporation is another form of electrically assisted transportation of molecules, where a quick voltage shock disrupts areas of the membrane temporarily and permeates drug molecules. For example, N. Crawford et. al. (U.S. Pat. No. 6,662,044) use a combination of iontophoresis and electroporation.
Recently, there have also been studies on microneedle based transdermal drug delivery patches, and the rationale behind this technology is that needles ranging from 100 to 1500 microns (opening diameter ranges from 10 to 300 microns) in lengths offer less painful and efficient route for transdermal drug delivery. Arrays of microneedles inserted across the stratum corneum have been shown to painlessly disrupt this barrier and increase the permeability of skin by several fold magnitude (i.e., without applying any active energy form). Microneedles arrays based substrates are typically based on metal (e.g., steel), polymer or biodegradable (e.g., polylactic acid, polyglycolic acid and their copolymers) or metal oxides (e.g., silicon dioxide). However, unfortunately, the efficiency of the micro needle technology is dependent on shape, width and size of the needle and the drug diffusion into the skin is passive and is not well controlled. For example Zeil B Rosenberg (U.S. Pat. No. 6,623,457) describes method of transdermal delivery of pharmaceutical agent by employing microneedles.
As outlined above varieties of energy forms (and an array of microneedles) have been used to transport the drug across the skin membrane, which may involve multitude of drug transport mechanisms. However, unfortunately, each energy form has its own preferred transport mechanism and may have limitations with regard to the number and type of drugs they could delivery across the skin membrane. Besides the drug permeation rates dramatically vary depending upon drug/formulation and the nature of energy form applied. In this regard, we propose the use of a single controller that provides a combination of energy sources/pulses to act upon a transdermal drug delivery patch (including microneedles based) with varying intensity, sequence, and timing to enable the transport of drugs using synergistic/cooperative transport mechanisms. As a consequence, application of multiple energy forms in a predetermined sequence/time intervals and intensities provides an excellent opportunity to permeate several small and large molecular drugs (including insulin and vaccines) and provides precise control over pharmacokinetics and drug transport mechanisms leading to the emergence of a single platform that treats multiple therapeutic indications that have been disclosed herein.
In this venture, we take advantage of recent advances in printed electronics/microneedle arrays to deliver drugs transdermally using a combination of transport mechanisms and energy sources, i.e., heat, sound and electromotive force, where a microprocessor controls the thermal/ultrasonic energy and electrical current applied to the skin in a programmable fashion (concurrently or alternately) to deliver drugs (e.g., insulin) with tunable pharmacokinetics for local and systemic drug delivery applications.
Further, the disclosure is intended to generate a new disposable active transdermal patch for delivering a variety of drugs (including insulin and vaccines) with controlled pharmacokinetics. Current transdermal drug delivery patches rely on unregulated energy sources and have limitations in delivering drugs of choice (i.e., small molecules to vaccines) e with controllable pharmacokinetics.